Abstract

I. Analysis of human lymphocyte mediated cytotoxicity. Effectors. Spontaneously cytotoxic polyclonally activated and antigen stimulated killer cells will be compared for lineage, stage of maturation, and release of cytotoxic factors. Do donors with different killing efficiencies to BEBV differ in the number of specific precursors? Can IFNs participate in BEBV inhibition? What is the relative importance of EBV-determined and EBV-independent B-blast structures in BEBV induced autologous T-cell responses? Target cell involved in the triggering of lytic interactions will be compared for membrane properties and antigenic expression. Is it possible to modulate the NK sensitivity of the B2M/class I antigen defective Daudi and K562 lines by B2M transfection? The role of C3 and split products in mediating complement dependent cytotoxicity (CDCC) will be studied with particular emphasis on its possible role as a surveillance mechanism. II. Genetic analysis of natural effector mechanism in the mouse. 13 congenic resistant strains are being developed, to carry a single gene that influences natural resistance to small grafts from an NK-sensitive Moloney lymphoma (YAC). In the previously identified 2 H-2 linked genes, NKD and NKT, that influence NK-mediated lysis, will be studied for interactions with each other and with the genetic background. The genetics of natural and immune resistance will be compared in selected tumor-host combinations. III. Studies on natural resistance against tumor cell variants with MHC class I losses or gains. Stable variants will be tested for susceptibility to NK lysis and natural resistance, with particular focus on i) the role of defined class I tumor/host mismatching: ii) the effector of changed class I antigen expression on growth properties in the syngeneic host and iii) the influence of changed H-2 expression on tumor cell immunogenicity and immunosensitivity. The H-2 loss and gain variants will also be compared for early elimination, pulmonary colonization and effector sensitivity in syngeneic and in specifically mismatched hosts. We shall also explore whether NK cells can protect the primary host of an autochthonous tumor that is non-immunogenic in the usual preimmunization-rejection test, from metastasis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA025250-09
Application #
3166771
Study Section
Immunobiology Study Section (IMB)
Project Start
1979-07-01
Project End
1989-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
9
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Karolinska Institute
Department
Type
DUNS #
350582235
City
Stockholm
State
Country
Sweden
Zip Code
171 77

  Publications

Stuber, G; Dillner, J; Modrow, S et al. (1995) HLA-A0201 and HLA-B7 binding peptides in the EBV-encoded EBNA-1, EBNA-2 and BZLF-1 proteins detected in the MHC class I stabilization assay. Low proportion of binding motifs for several HLA class I alleles in EBNA-1. Int Immunol 7:653-63
Vegh, Z; Wang, P; Vanky, F et al. (1994) Cytotoxic susceptibility and defective MHC class I expression do not correlate with mutation of p53 in human carcinomas. Cancer Immunol Immunother 38:71-3
Avila-Carino, J; Lewin, N; Yamamoto, K et al. (1994) EBV infection of B-CLL cells in vitro potentiates their allostimulatory capacity if accompanied by acquisition of the activated phenotype. Int J Cancer 58:678-85
Altiok, A; Di Renzo, L; Altiok, E (1994) Influence of transforming growth factor-beta (TGF-beta) on the immunoglobulin production by EBV-infected B cell cultures. Immunol Lett 43:199-202
Altiok, A; Jadersten, M; Magyarlaki, T et al. (1994) Biphasic effect of transforming growth factor-beta on Epstein-Barr virus-induced activation of human tonsillar B cells. Immunol Lett 40:111-5
Klein, E (1993) Reflections on human tumor immunology. Med Oncol Tumor Pharmacother 10:83-6
Algarra, I; Silva, S; Ljunggren, H G (1993) MHC class I expression on prelymphomatous and lymphomatous B-cells is not inhibited by an E mu-myc transgene. Eur J Cancer 29A:238-41
Vegh, Z; Wang, P; Vanky, F et al. (1993) Selectively down-regulated expression of major histocompatibility complex class I alleles in human solid tumors. Cancer Res 53:2416-20
Klein, E; Mantovani, A (1993) Action of natural killer cells and macrophages in cancer. Curr Opin Immunol 5:714-8
Kuraya, M; Minarovits, J; Okada, H et al. (1993) HRF20/CD59 complement regulatory protein expression is phenotype-dependent and inducible by the hypomethylating agent 5-azacytidine on Burkitt's lymphoma cell lines. Immunol Lett 37:35-9

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